Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury.

Antituberculosis drug-induced liver injury (ATDILI) is the most prevalent hepatotoxicity in many countries. All of the three first-line antituberculosis drugs, isoniazid, rifampicin, and pyrazinamide, may induce hepatic damage, especially isoniazid. The major drug-metabolizing enzyme of isoniazid is N-acetyltransferase (NAT). Other possible enzymes are CYP2E1, glutathione S-transferase (GST) and manganese superoxide dismutase (MnSOD, SOD2). There is evidence that variations of the genes that encode these enzymes may influence the activity of the corresponding drug-metabolizing enzymes. Recent studies have demonstrated that these genetic variations may be associated with the risk of ATDILI. Among them, NAT acetylation status has been most studied. The proposed risk-associated genotypes are NAT2 slow acetylator (without wild-type NAT2*4 allele), CYP2E1 *1A/*1A (homozygous wild type), homozygous null GSTM1 genotype and MnSOD mutant C allele. Although the available data in the field are complex and inconsistent, meta-analyses disclosed that NAT2 slow acetylator status possesses the highest association (odds ratio = 3.18). There are associations of CYP2E1 *1A/*1A and homozygous null GSTM1 genotype with ATDILI by meta-analyses, but the odds ratios were lower than that of NAT2. Of note, there was an ethnic difference in this association. The ATDILI in East Asians seems to have a higher correlation with genetic variations of NAT2, CYP2E1 and GSTM1. However, the meta-analyses could not validate these associations in Caucasians, although some showed positive correlations. To mitigate the crucial ATDILI, this review article underlines the importance of this pharmacogenetic endeavor to identify high-risk patients.

Arylamine Acetyltransferase Activity from a Regenerating Liver after Partial Hepatectomy and from a Cholestatic Liver after Common Bile Duct Ligation in Rats

A study was made of the change in arylamine acetyltransferase(AAT) activity in regenerating and/or cholestatic rat livers. Cytosolic, mitochondrial and microsomal AAT activities were determined over a period of 10 days in rat livers which were regenerating after 70%(median and left lateral lobes) partial hepatectomy and over a period of 42 days in rat livers with cholestasis induced by a common bile duct ligation. The values of Km and Vmax in these hepatic enzymes were measured. Both the cytosolic and the microsomal AAT activities in the regenerating rat livers showed significant increases from the first day to the third day after the partial hepatectomy. However, the mitochondrial AAT activity did not change. The cytosolic and the microsomal AAT activities in the cholestatic rat livers showed a significant increase on the first day and from the first day to the second day, respectively after the ligation; Both the cytosolic and the microsomal AAT activities showed significant decreases from the fourteenth day to the forty-second day after the ligation. However, the mitochondrial AAT activity did not change. The Vmax values of both the cytosolic and the microsomal AAT activity in the regenerating and/or cholestatic rat livers showed significant increases on the first day after the partial hepatectomy and/or the ligation. However, the Vmax values of both the cytosolic and the microsomal AAT activities in the cholestatic rat livers showed significant decreases on the twenty-eighth day after the ligation. On the other hand, the Km values of the above enzymes did not change. In view of the above results, the AAT activity in the regenerating rat liver appears to be due to the enzyme increasing its biosynthesis in the regenerating stage. The AAT activity in the cholestatic rat liver suggests that the enzymes is increasing its biosynthesis in the severe necrotizing stage, but decreasing its biosynthesis severe hepatic dysfunction stage.